One of my colleagues at the Colorado Mesa University Monfort Family Human Performance lab is Carmine Grieco, PhD, an exercise physiologist. It has been interesting to hear Carmine’s perspective on Exercise is Medicine, as he has been involved at the research level and is very interested in the effects of exercise on Type 2 Diabetes. Carmine and I wrote a four-part series for Personal Training Quarterly (PTQ) discussing the impact of exercise on chronic disease. For that series, we started with the impact of exercise on Type 2 Diabetes and then discussed exercise and the brain - that article is below. Clearly, exercise should play a critical role in the overall treatment plan for patients. (Please note: Patients with diabetes and any other chronic disease or condition should first discuss a change in exercise levels or habits with their medical provider)

This article is the second in a 4-part series which will explore the impact of exercise on a variety of diseases and conditions. As fitness professionals we have a deep understanding of the positive effect exercise has on health and human performance. Despite the efficacy of exercise as both a preventive and treatment for a wide range of diseases and conditions, standard medical interventions (notably pharmaceuticals) remain the “go to” medical option for most individuals. In fact, recent estimates by the National Center for Health Statistics suggest that nearly 50% of the U.S. population have used a prescription drug within the last 30 days (1). The aim of this article series is to provide a context for understanding the efficacy of exercise as a therapeutic intervention and adjunct therapy with a comparison to commonly prescribed treatments.

Diseases and disorders affecting cognitive capability, such as depression and Alzheimer’s disease, are among the most common and costly in the United States (2). Exercise is a cost-effective treatment for cognitive disease and shows promise as an adjunctive or primary therapy, as well as means of prevention (3, 4, 5). The impact of exercise goes beyond treating disease and extends to enhancing cognitive performance as well. Therefore, in this second part of our 4-part series we will explore the efficacy of exercise on academic performance, Alzheimer’s disease and depression.

Physical Activity and Academic Performance

Evidence has demonstrated decreasing levels of physical activity and fitness in children with an associated increase in the incidence of obesity in youth (6, 7) In fact, there is evidence that as many as one in six children are obese (6). Obesity increases the risk of diabetes, high blood pressure, and cardiovascular disease, for all ages (8). In addition to short and long-term overall health consequences, there is strong evidence linking obesity with reduced cognitive and academic function (9).

The relationship between physical fitness/physical activity and academic achievement is robust and consistently positive (10, 11, 12, 13, and 14). Physical activity and fitness are associated with both acute and chronic improvements in cognitive function (11). In 1997, Etnier et al. published one of the earliest reviews showing the benefit of children’s physical activity (PA) on cognitive performance (12). The results of their evaluation of 134 studies suggested that both acute and chronic exercise benefited cognitive performance, although there were limitations secondary the cross-sectional and correlational design. During the last 15 years, there has been a significant increase in the literature looking at PA and learning in children. This literature has looked at brain structure and function as well as cognition. This includes cognitive control, which comprises working memory, goal-directed behavior involving inhibition, and mental flexibility; all important in the classroom (15).

Many of those early studies, showed that aerobic fitness in children was positively associated with academic performance and cognition (16, 17). Specifically, evidence showed that students with higher aerobic fitness demonstrate improved academic performance and achievement compared to their unfit counterparts (16, 18, 19). Interestingly, aerobic training seems to enhance neurotransmitters (20) and the production of brain derived neurotrophic factor or BDNF, which has been called the “Miracle-Gro” of the brain, by psychiatrist John Ratey (21).

For example, Donnelly et al. conducted a three-year study that involved 24 elementary schools and began with children in grades two and three and followed them for three years (10). The 24 elementary schools were divided into either control or intervention groups. The control group schools were already doing 60 min of PE classes weekly and they maintained that for the length of the study. The intervention group, also doing 60 minutes of PE class every week, added an additional 90 minutes of “in-class” activities scattered throughout the week. These were short bursts of activity of about 10 minutes each, which were conducted intermittently throughout the day, not in PE class, but in the regular classroom setting.

Academic achievement, as assessed by the Wechsler Individual Achievement Test, 2ndEdition (WIAT-II), improved significantly for the intervention group in math (~+8%), spelling (~+4%), and composite scores (~+5.5%), in comparison to the control group, which saw decreases in reading (~-2%), spelling (~-0.5%), and composite scores (~-0.5%), with only a modest increase in math scores (~+1%). This study provides two important insights. Firstly, despite the intervention group incorporating an additional 90 minutes of exercise into the school week, which reduced standard learning time, they achieved higher scores on a standardized test of academic achievement. Secondly, it also demonstrates that following the recommended guidelines promoting a minimum of 150 minutes of PA every week can actually improve academics.

More recent studies have looked at the importance of muscular fitness in cognition and learning. Muscular fitness demonstrates multiple health benefits for children including a reduced risk of metabolic and cardiovascular disease, improved bone health and decreased obesity. These factors point to enhanced cognition by themselves (22). A study of 1700 students looking at fitness factors, found that muscular strength and endurance were the most significant factors associated with academic achievement in all grades (13). More recently, Kao et al. showed the importance of muscular fitness and working memory, illustrating the importance of muscular strength and endurance on cognition in preadolescents (14).

The Naperville, Illinois school district is an often-used illustration of the benefits of exercise for students (23). Their physical education instructors changed from competitive team sports to movement based activity using heart rate monitors, along with other purposefully interactive activities. They found improvements in academic scores, lower levels of obesity, improved attendance and less behavioral problems associated with regular activity. This has been replicated in schools of different sizes and varied socioeconomic levels (13, 24). As an example, a large study involving the California school system explored the relationship of fitness and academics. The data illustrates a consistently positive relationship with fitness levels and scores in both math and reading achievement tests (24, 25). In addition, there is no evidence for a detrimental change from adding physical activity to the school day, even when taking time away from academic study (26).

More recently, there has been more consideration of the importance of “moving with thought” or an integrative exercise program, to enhance brain activity and cognitive benefit. These studies and programs are looking at what combination of exercise and cognitive activity will have the greatest impact; looking beyond running on the treadmill to interesting activities that promote brain activity (15, 27). An example is the improvement in executive function seen with traditional martial arts, such as Tae Kwon Do (28).

There is still much to learn about this exciting topic, such as the exact type and timing of exercise that imparts the greatest impact for learning in children and others. In addition to these academic benefits, children will enjoy many other health benefits from exercise and physical activity. Overall, there is clear evidence for the impact and importance of exercise, movement and fitness on the future health and academic success of children.

Alzheimer’s Diseas

The aging of the American population has brought special emphasis on the impact of dementia on society. Dementia is a broad term that describes memory loss and cognitive impairment that is severe enough to interfere with daily life. The development of dementia becomes a concern for many as we age and is a burden to the affected patients and families as well as our healthcare system. The most common form of dementia, Alzheimer’s disease (AD), affects over 5 million Americans and is the 6thleading cause of death in the U.S. Moreover, the number of Americans living with AD is growing and the prevalence is expected to triple by 2050 (29). Interestingly, cognitive decline and dementia incidence varies in populations. While there are relationships with genetic and environmental causes, there is increasing evidence that over 25% of cases of AD are related to risk factors that are modifiable, such as physical inactivity and diet (30).

While pharmaceuticals have no known neuroprotective effect on the prevention of dementia, there is mounting evidence for the benefit of long-term, regular exercise on cognition and decreasing the incidence and progression of dementia. The initial observational studies showed improvement in cognitive scores, information processing and executive function after primarily aerobic exercise (31). More recently, in senior women with mild cognitive impairment there is good evidence for improvement in working memory and executive function after resistance training (32, 33).

When looking at age-related cognitive changes, there appears to be several factors that promote a cognitive decline, such as systemic inflammation, change in blood supply and actual structural change or atrophy. Exercise has been shown to impact all three of these areas; by increasing blood supply, decreasing inflammation (34, 35) and apparently increasing the volume or structure of the brain. Exercise “turns on” cognitive development and neuroplasticity secondary to the ability of the brain to form new neurons and synapses and improving blood supply. Neurotrophic factors, such as the previously mentioned BDNF, are felt to combat age-related brain atrophy and possibly neurodegenerative diseases (31). BDNF has been shown to be decreased in the brains of patients with AD, but it appears to be released after exercise (31).

Additionally, Erickson et al. showed an increase in the size of the hippocampus volume in a group of older adults related to an increase in VO2max (36). Other studies have shown that the hippocampus, which is essential to new memory and learning, appears to be positively responsive to exercise. Another study by Colcombe et al. illustrated that other areas of the brain increased in volume with exercise as well, as they showed that exercise in previously sedentary adults who began exercising increased their grey matter, essential to processing information, by 32% (37). A much larger study by Defina, et al. objectively evaluated the fitness of men and women beginning in their 50’s and followed them over the next 25 years and found the most fit subjects decreased their chance of developing dementia by 36% (38). Looking at the diagnosis of mild cognitive impairment, a condition which significantly increases the risk of developing AD, Baker et al. showed that the non-pharmacologic intervention of aerobic exercise, improved executive control and cognition in older women at risk of cognitive decline (39). Dr. Baker and others continue to look at “Exercise as Medicine for the Brain” in the EXERT trial (Exercise in Adults with Mild Memory Problems) (40). They have seen positive results on memory, increased blood flow to the brain, improved brain volume and improvement in markers of AD in several small studies (40).

Unfortunately, there are no curative pharmaceutical treatments for dementia. Some medications have been shown to improve symptoms but their effectiveness wanes as the disease progresses. The medications include acetylcholinesterase inhibitors such as donepezil (Aricept), N-methyl-D-aspartate (NMDA) blockers, such as memantine (Namenda) and other medications for the associated behavioral changes of dementia. The overall effectiveness of the medications appears modest but can be significant to the patients who can tolerate them. There are many clinical trials involving newer medications that may be able to impact these difficult diseases. Medications are a part of the successful care of patients with AD.

An integrative exercise program can address multiple domains of the brain as well as many areas of healthy aging. Overall, long-term physical activity simply improves the quality of life as we age. Therefore, it is imperative for fitness professionals to appreciate the many benefits of exercise and to encourage safe, enjoyable and interactive physical activity in people of all ages.

Depression

Depression is among the most common mood disorders and affects approximately 7.6% of Americans over the age of 12 annually (41). The first-line prescribed treatments for depression are psychotherapy, pharmaceutical antidepressants, or a combination of the two. Antidepressants are among the most frequently prescribed drugs in the U.S. and the rate of usage has increased significantly over the last 15 to 20 years, while psychotherapy rates have declined, indicating a shift toward pharmaceutical intervention for depressive disorders (42). For example, 6.8% of U.S. adults had used an antidepressant within the previous 30-day period in 1999/2000, while 2011/2012 data show a near doubling rate of use, which increased to 13% (43).

The American Psychiatric Association’s Practice Guideline for the Treatment of Patients with Major Depressive Disorderacknowledges both aerobic and resistance exercise confer “a modest improvement in mood symptoms for patients with major depressive disorder,” although exercise is not an initial suggested treatment modality (44). Nevertheless, the effect of exercise, particularly aerobic exercise, compares favorably to antidepressants.

Earlier work on the effect of exercise as a treatment for depression was promising. Blumenthal et al. randomized 156 older patients with major depressive disorder (MDD) to one of three groups: 1) aerobic exercise (thrice weekly exercise sessions at 70-85% of heart rate reserve, 2) Sertraline (Zoloft), a selective serotonin re-uptake inhibitor (SSRI), or 3) a combined therapy group, in which patients received both Sertraline and aerobic exercise (45). Following 16 weeks of therapy all three groups experienced significant improvements in mood, with no statistically significant difference among groups. Based upon these findings the authors concluded that exercise is a viable treatment option for depression, achieving decreases in depression scores comparable with drug therapy

More recently, meta-analyses by Stathopoulou et al. and Rethorst et al. found large and significant effect sizes favoring exercise over either non-intervention (i.e. no treatment or waitlist control) or minimal intervention (placebo treatment, low-level exercise or health education) control groups in clinical populations diagnosed with depression (effect sizes of 1.42,and 1.07, respectively)(46, 47). While these meta-analyses (and others) have found a strong and consistent association between exercise and a positive mood-altering effect, the quality of randomized controlled trials investigating the effect of exercise as an antidepressant therapy have been called into question (48).

A meta-analysis published in 2016 sought to address these limitations and quantify the strength of existing evidence (49). Schuch et al. also reported a large mood-enhancing effect of exercise, with an effect size similar to that reported by Stathopoulou et al. and Rethorst et al. (1.11). The authors concluded that there is “robust evidence that exercise can be considered an evidence-based treatment for the management of depression.” Moreover, exercise therapy also compares favorably with psychotherapy for the treatment of depression. A recent meta-analysis by Cooney et al. concluded that exercise was equally effective as both psychotherapy and pharmacological treatment in reducing depression symptoms (50).

No organization has yet published a position statement regarding the appropriate duration, frequency, intensity or type of exercise necessary to achieve an antidepressant effect, however a recent meta-analysis by Rethorst and Trivedi provides evidence-based recommendations (47). Exercise prescription guidelines include:

Modality: Aerobic exercise is well represented in the literature for its antidepressant effect. Resistance training shows promise, however, there is a limited amount of research to date.

Frequency: A minimum of three sessions per week

Duration: 45-60 minutes per session.

Intensity: 50-85% of heart rate max for aerobic exercise. Resistance training should consist of both upper and lower body exercises for 3 sets of 8 repetitions at 80% of 1RM.

While more research is indicated to fully illuminate the effect of exercise on depression, as well as identifying the mechanisms through which exercise effects mood, the preponderance of evidence suggests that exercise is an efficacious mode of treatment. Both pharmacotherapy and psychotherapy play a fundamental role in the treatment of depression, nevertheless, it is becoming recognized and accepted that exercise can, and should, play a more prominent role in overall treatment of depressive disorders.

Conclusion

Exercise is an underutilized therapy for the treatment of cognitive diseases such as Alzheimer’s disease and depression. While exercise shows more promise for the prevention, rather than the treatment, of Alzheimer’s disease, exercise therapy compares favorably to the most common treatments of depression: psychotherapy and antidepressants. Moreover, there is mounting evidence that exercise exerts a positive effect on cognition in older adults, as well as demonstrating an ability to improve cognitive performance in children, as evidenced by improvements in standardized testing.

References

1. National Center for Health Statistics. Health, United States, 2015: With special feature on racial and ethnic health disparities. Hyattsville, MD. Retrieved December, 2016 from http://www.cdc.gov/nchs/data/hus/hus15.pdf#079.

42. Marcus SC and Olfson M. National trends in the treatment of depression from 1998 to 2007. Archives of General Psychiatry67(12): 1265-1273, 2010.

43. Kantor ED, Rehm CD, Haas JS, Chan AT, and Giovannucci EL. Trends in prescription drug use among adults in the United States from 1999 to 2012. Journal of the American Medical Association314(17): 1818-1831, 2015.

44. American Psychiatric Association. Practice Guidelines for the Treatment of Patients with Major Depressive Disorder, 2010.https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdfAccessed on 08 March, 2017.

47. Rethorst CD and Trivedi MH. Evidence-based recommendations for the prescription of exercise for major depressive disorder. Journal of Psychiatric Practice19(3): 204-212, 2013.

48. Lawlor DA and Hopker SW. The effectiveness of exercise as an intervention in the management of depression: Systematic review and meta-regression analysis of randomized controlled trials. BMJ322(7289): 763-767, 2001.

Protective Effects of Exercise on the Brain

As we know, we are living in an aging world. The Population Reference Bureau predicts that the number of Americans ages 65 or older is projected to double from almost 50 million to nearly 100 million in the next 40 years and this group will make up 24% of the total population of the United States at that time. As advancing age is associated with the development of dementia, these increases will bring challenges to patients, families and our health care system. As we have discussed before, exercise or physical activity is an important intervention in the prevention and treatment plans related to cognitive change. Addressing this issue, a recent article from the University of Calgary reviewed the protective effects of exercise on cognition and brain health.

In their article, Tyndall et al note that post maturation aging is accompanied by multiple adverse changes that contribute to cognitive decline. These include changes in biomarkers such as an increase in low-grade inflammation, increase in oxidative stress and a decrease in growth factors, such as growth hormone and neurotropic factors. Other changes include both psychological, mood changes, and physiological, such as a decrease in fitness and cerebrovascular function. Evidence suggests that physiologic changes, such as the decrease in cerebral blood flow, leads to hypoperfusion. Cerebral hypoperfusion is strongly linked to increased risk of cognitive dysfunction and dementia. In addition to these factors, lifestyle choices such as smoking, excessive alcohol use and poor diet contribute to overall brain health.

The beauty of our human design is that exercise or physical activity directly addresses these areas of change with aging. Exercise has been shown to decrease inflammation and oxidative stress while modulating neurotrophic factors. Related to psychological factors, multiple studies have shown improvement in mood, enhanced sleep and improvement in depression with exercise. During exercise, there is evidence of increased cerebral blood flow acutely and with chronic exercise, there is an improvement in hippocampal volume. When looking at cognition in older adults, studies show a direct relationship between cognitive abilities and higher VO2max. Emphasizing the importance of being a lifelong exerciser, there is interesting evidence that lower levels of cardiorespiratory fitness in early adulthood are related to a higher chance of cognitive impairment and dementia risk later in life.

Again, encouraging increased physical activity in everyone is an essential part of our roles as medical providers. We should encourage everyone to have an active day.